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EC number: 201-377-6 | CAS number: 81-81-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Well-documented materials and methods section with appropriate number of animals per group and time point. No controls used. Only 1 dose group. Did not include excretion, or metabolism parameters. No GLP compliance reported.
Cross-reference
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- publication
- Title:
- Gender Differences in Pharmacokinetics of Oral Warfarin in Rats
- Author:
- Zhu X, Shin WG
- Year:
- 2 005
- Bibliographic source:
- Biopharmaceutics and Drug Disposition, 26: 147-150
Materials and methods
- Objective of study:
- toxicokinetics
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Principles of method if other than guideline:
- The purpose of the study is to determine gender differences in the pharmacokinetics of oral warfarin in rats.
- GLP compliance:
- not specified
Test material
- Reference substance name:
- Warfarin
- EC Number:
- 201-377-6
- EC Name:
- Warfarin
- Cas Number:
- 81-81-2
- Molecular formula:
- C19H16O4
- IUPAC Name:
- 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one
- Details on test material:
- - Name of test material: Warfarin.
Constituent 1
- Radiolabelling:
- no
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Samtako Bio Korea (Seoul, Republic of Korea.)
- Age at study initiation: 7 weeks.
- Weight at study initiation: 250-320 grams.
- Fasting period before study: Overnight.
- Individual metabolism cages: Yes.
- Diet: Ad libitum.
- Water: Ad libitum.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23 degrees Celcius.
- Humidity (%): 50%.
- Photoperiod (hrs dark / hrs light): 12 hours light, 12 hours dark.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- The procedures for the pretreatment of rats including the cannulation of the carotid artery in the early morning of the experiment were reported previously. Rats were lightly anaesthetized with ether and the experiment was started 4–5 hours after surgery. Warfarin was administered orally (total oral volume of approximately 1.5 ml) to male and female rats using a feeding tube.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
2mg/kg.
- No. of animals per sex per dose / concentration:
- 10 per sex per same dose.
- Control animals:
- no
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: Blood.
- Time and frequency of sampling: Approximately a 0.22 ml blood sample was collected via the carotid artery in an Eppendorf tube containing a 30 ml aliquot of 3.8% sodium citrate (to prevent blood clotting) at 0 (to serve as a control), 0.5, 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours. Blood samples were centrifuged immediately and a 100 ul aliquot of each plasma sample was stored in a -70 degrees Celcius freezer until HPLC analysis.
- Other: The concentrations of warfarin in the above plasma samples were analysed by the reported HPLC method (1.)
- Statistics:
- A value of p<0.05 was considered to be statistically significant using an unpaired t-test. All data are expressed as mean +/- standard deviation.
Results and discussion
Toxicokinetic / pharmacokinetic studies
Toxicokinetic parametersopen allclose all
- Test no.:
- #1
- Toxicokinetic parameters:
- AUC: 180 +/-52.0 in males; 345+/-80.0 in females
- Test no.:
- #2
- Toxicokinetic parameters:
- Cmax: 7.13+/-3.12 in males; 7.53+/-1.29 females
- Test no.:
- #3
- Toxicokinetic parameters:
- Tmax: 6 in males; 12 in females
- Test no.:
- #4
- Toxicokinetic parameters:
- other: Terminal half-life in males = 16.1+/-5.43; in females = 28.4 +/-8.32
Metabolite characterisation studies
- Metabolites identified:
- not measured
Any other information on results incl. tables
After oral administration of warfarin to male and female rats, concentrations declined thereafter (Cmax) in a monoexponential fashion for all rats studied. In female rats, the plasma concentrations of warfarin were higher after Tmax than those in male rats. This resulted in a significantly greater AUC of warfarin in female rats (91.7% increase).
The slower metabolism of warfarin in female rats could be at least partly supported by the significantly longer terminal half-life of warfarin (76.4% increase). In female rats, the plasma concentrations of warfarin were lower up to Tmax and the Tmax was significantly longer (78.5% increase) suggesting that warfarin is absorbed more slowly in female rats.
Table 1
Mean (+/- standard deviation) pharmacokinetic parameters of warfarin
after oral administration at a dose of 2mg/ kg to male and female rats
Parameter |
Male (n = 10) |
Female (n= 10) |
AUC (ug h/ml) |
180 +/- 52.0a |
345 +/- 80.0 |
Cmax (ug/ml) |
7.13 +/- 3.12 |
7.53 +/- 1.29 |
Tmax (h)b |
6 (1-12)c |
12 (8-24) |
Terminal half-life (h) |
16.1 +/- 5.43a |
28.4 +/- 8.32 |
aSignificantly different (p<0.001) from female rats.
bMedian (range).
cSignificantly different (p<0.05) from female rats
Applicant's summary and conclusion
- Conclusions:
- After oral administration of warfarin to female rats, the AUC was significantly greater (345 compared with 180 ug h/ml) than that in male rats.
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